Goodpasture antigen binding protein (GPBP) is a ubiquitous protein kinase with a Mr of 80-89 kDa that is preferentially expressed in tissues and cells that are common targets of autoimmune responses, such as the Langerhans islets (type I diabetes); the white matter of the central nervous system (multiple sclerosis); the biliary ducts (primary biliary cirrhosis); the cortical cells of the adrenal gland (Addison disease); striated muscle cells (myasthenia gravis); spermatogonium (male infertility); Purkinje cells of the cerebellum (paraneoplasic cerebellar degeneration syndrome); and intestinal epithelial cells (pernicious anemia, autoimmune gastritis and enteritis).
GPBP is expressed as two isoforms (GPBP and GPBPΔ26) which result from exon alternative splicing of the corresponding pre-mRNA. GPBP is the more active variant, and its expression is still more restricted to histological structures targeted by common autoimmune responses including human alveolar and glomerular basement membranes (Goodpasture disease). GPBP binds to and phosphorylates the human α3 NC1 domain of type IV collagen (α3(IV)NC1) also called the Goodpasture antigen (WO 00/50607), as this domain is the target of the pathogenic autoantibodies mediating the Goodpasture autoimmune response. Phosphorylation activates the α3(IV)NC1 domain for aggregation, a process that is catalyzed at least in part by GPBP and which comprises conformational isomerization reactions and disulfide-bond exchange (WO 02/061430).
An augmented expression of GPBP with respect to GPBPΔ26 has been associated with the production of non-tolerized, aberrant conformational versions of the human α3(IV)NC1 domain (“aberrant conformers”) and the subsequent autoantibody production that causes Goodpasture disease (WO 02/061430). The evidence suggests that a similar pathogenic mechanism is involved in other autoimmune conditions, including cutaneous lupus erythematosus, pemphigus, pemphigoid and lichen planus, and that aberrant GPBP expression and autoimmune pathogenesis are related processes. Furthermore, GPBP is down-regulated in cancer cell lines (WO 00/50607), suggesting that the cell machinery harboring GPBP/GPBPΔ26 is also involved in signaling pathways that decrease cell division or induce cell death. These pathways could be up regulated during autoimmune pathogenesis to cause altered antigen presentation in individuals carrying specific MHC haplotypes, and down regulated during cell transformation to prevent autoimmune attack of the transformed cells during tumor growth.
Based on all of the above, there exists a need in the art to identify methods and reagents for modifying GPBP activity for use in treating autoimmune disorders and cancer.